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Lipopolysaccharide Inhalation Recruits Monocytes and Dendritic Cell Subsets to the Alveolar Airspace

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Lipopolysaccharide Inhalation Recruits Monocytes and Dendritic Cell Subsets to the Alveolar Airspace ARTICLE https://doi.org/10.1038/s41467-019-09913-4 OPEN Lipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace Laura Jardine 1,2,4, Sarah Wiscombe1,2,4, Gary Reynolds1,2, David McDonald1, Andrew Fuller1, Kile Green1, Andrew Filby1, Ian Forrest2,Marie-HeleneRuchaud-Sparagano1, Jonathan Scott1, Matthew Collin1,2, Muzlifah Haniffa 1,3,4 & A. John Simpson1,2,4 Mononuclear phagocytes (MPs) including monocytes, macrophages and dendritic cells 1234567890():,; (DCs) are critical innate immune effectors and initiators of the adaptive immune response. MPs are present in the alveolar airspace at steady state, however little is known about DC recruitment in acute pulmonary inflammation. Here we use lipopolysaccharide inhalation to induce acute inflammation in healthy volunteers and examine the impact on bronchoalveolar lavage fluid and blood MP repertoire. Classical monocytes and two DC subsets (DC2/3 and DC5) are expanded in bronchoalveolar lavage fluid 8 h after lipopolysaccharide inhalation. Surface phenotyping, gene expression profiling and parallel analysis of blood indicate recruited DCs are blood-derived. Recruited monocytes and DCs rapidly adopt typical airspace-resident MP gene expression profiles. Following lipopolysaccharide inhalation, alveolar macrophages strongly up-regulate cytokines for MP recruitment. Our study defines the characteristics of human DCs and monocytes recruited into bronchoalveolar space immediately following localised acute inflammatory stimulus in vivo. 1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. 2 Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK. 3 Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK. 4These authors contributed equally: Laura Jardine, Sarah Wiscombe, Muzlifah Haniffa, A. John Simpson. Correspondence and requests for materials should be addressed to L.J. (email: [email protected]) or to M.H. (email: [email protected]) NATURE COMMUNICATIONS | (2019)10:1999 | https://doi.org/10.1038/s41467-019-09913-4 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09913-4 he alveoli of the lung present a large but fragile surface events in human lung inflammation. Eight MP subsets can be area to the environment. Maintaining the integrity of identified in steady state BAL following sterile saline inhalation Tthe alveolar-capillary membrane is critical to effective gas (SS-BAL), in line with subsets described in blood. Monocytes and exchange. Immune regulation at this interface must control two myeloid DC subsets (DC2/3 and DC5) are recruited as early infection and limit immunopathology. Mononuclear phagocytes as 8 h following LPS inhalation (LPS-BAL) and rapidly adopt (MPs), comprising monocytes, macrophages, and dendritic cells gene expression profiles characteristic of airspace MP residence. (DCs) have a critical role at any environmental interface as innate The cytokine and chemokine profile of BAL implicates AMs as immune effectors equipped to shape the adaptive immune the likely instigator of blood monocyte and DC recruitment into response through antigen presentation, co-stimulation, and the alveolar airspace during acute inflammation. cytokine production. Leukocytes from the alveolar airspace can be readily isolated by bronchoscopy and bronchoalveolar lavage (BAL). BAL has been Results less extensively characterized than lung tissue but presents a Accumulation of alveolar neutrophils, monocytes, and DCs. number of advantages as a window to the lung’s immune system: The steady state MP repertoire of BAL was defined by flow BAL yields a cell suspension free from contaminating blood cytometry in healthy individuals 8 h after inhalation of isotonic leukocytes with minimal processing requirement thus preserving saline (Fig. 1a, Supplementary Fig. 1). We used a recent surface antigens and native activation status. description of human blood MP diversity based on single cell MPs in any anatomical compartment are a heterogeneous RNA-sequencing as a template for identifying BAL MP popula- group of leukocytes. Establishing the steady-state repertoire of a tions19. As an adaption for BAL analysis, we first used side scatter compartment is crucial to understanding infiltrates seen in and CD45 expression to exclude CD45loSSCmid neutrophils and inflammation. Most tissues contain embryonically-derived mac- identify alveolar macrophages (AM) as CD45+SSChi cells (Sup- rophages with variable contributions from circulating monocytes plementary Fig. 1). BAL CD45+SSClo cells were then comparable depending on how available the tissue niche is1,2. Monocyte- to peripheral blood mononuclear cells (PBMC) (Fig. 1b). Per- derived cells are observed adopting a spectrum of macrophage ipheral blood was sourced from healthy controls (HC) that had or DC features depending on the tissue. While steady state not received inhalation challenge. CD45+SSClo cells that monocyte-derived DCs are observed in mouse skin and gut3–5, expressed HLA-DR but not lineage markers (CD3, 19, 20, 56) their existence in human tissues has not been convincingly were gated into CD14++CD16−, CD14++CD16+, and CD14+ established. DCs are broadly divided into plasmacytoid DCs CD16++ fractions analogous to blood classical, intermediate and (pDC) that characteristically produce IFN-α and conventional non-classical monocytes, respectively. The CD14−CD16− frac- DCs (cDC) that effectively stimulate T cell proliferation6. Two tion containing DCs was first probed for the rare Axl+Siglec6+ subsets of cDCs with homology across species have been clearly population (DC5) as its varied expression of CD123 and CD11c identified. cDC1 expresses CD141, CLEC9A, and XCR1 in would otherwise place it within pDC and cDC gates. After DC5 humans and is adept at cross-presenting antigen7–11. cDC2 exclusion, CD123+CD11clo cells identified pDC and further expresses CD1c in humans and is important for activation of CD4 segregation of the CD11c+ cells using a combination of BTLA T cells, induction of regulatory T cells and activation of Th2 and and CD1c identified DC1 and DC2/3. While DC1 is most typi- Th17 responses12,13. cally defined by its expression of CD141 or CLEC9A, immune A number of recent studies have capitalized on multi- gene expression by cells sorted from the BTLAhi gate expressed parameter flow cytometry to define subsets of MPs across the expected gene profile of DC1, confirming the validity of this human lung compartments14–18, but differences in approach have approach (Supplementary Fig. 1). We did detect a population led to continued debate about whether rare DC subsets (pDC and of CD11c+CD1c−BTLA− cells within our DC gate, which are cDC1) exist in BAL or have been inadvertently excluded during likely to correspond to DC4 described in Villani et al., but can analysis. As blood is a source of tissue-recruited leukocytes, a only refer to these as CD11c+CD1c− cells without further logical approach would use blood MP definitions to classify tissue characterization. MPs. Recent insights from single cell RNA sequencing have The dominant MP subset in SS-BAL was the AM (Table 1). revealed additional complexity in our understanding of blood Comparing SS-BAL CD45+SSClo cells with PBMC, MPs were MPs, including the presence of previously undiscovered DC richer in SS-BAL (Table 1). Of MPs, the most abundant subset subsets, and heterogeneity within existing subsets19. Briefly, this was a CD14++CD16+ population (Table 1; Fig. 1d). CD14++ confirmed the presence of cDC1 (DC1) and pDC (pDC or DC6). CD16− cells, analogous to classical monocytes in blood, were It revealed two subdivisions within cDC2 (DC2, DC3) and comparatively rare in SS-BAL and CD14+CD16++ cells, identified additional DCs subsets: Axl+Siglec−6+ DCs (AS DC analogous to non-classical blood monocytes, were virtually or DC5) and CD1c-CD141− DCs (DC4). To date, this revised absent. All DC subsets, especially CD1c-expressing DC1 and classification has not been tested in non-lymphoid tissue. DC2, were enriched in SS-BAL relative to blood. As our understanding of the BAL MP repertoire in steady state Following LPS inhalation, the greatest leukocyte expansion was develops, it becomes tangible to address the question of what in CD14++CD16− MPs (400-fold difference in mean concentra- happens during inflammation. In mice, inflammatory macrophages tion between SS-BAL and LPS-BAL), followed by neutrophils and DCs have been described in numerous infection and sterile and DCs (Fig. 1c). Amongst DCs, the concentrations of CD1c+ inflammation models20–25. Monocytes are thought to be the source DCs (DC2/3) and DC5 were selectively increased (Fig. 1c). of inflammatory DCs, based on studies in CCR2 and Flt3-deficient To examine the impact of acute lung inflammation on animals and adoptive transfer of monocytes20–24.Distinctinflam- peripheral blood MP populations, their concentrations were matory macrophages and DCs have also been identified in human tracked at 2-h intervals following inhalation of LPS or saline chronic inflammatory exudates26.Theseinflammatory DCs are (Fig. 1e). Neutrophils, which were abundant in LPS-BAL and proposed to arise from monocytes based on transcriptional simi- pDCs, which were not enriched in LPS-BAL, were tracked for larity to in vitro monocyte-derived DCs26.Earlytime-pointsof comparison with monocytes and DCs. Following saline inhala- inflammation have not been adequately
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